Transdermal drug delivery systems have, in recent years, become an increasingly important means of administering drugs and like therapeutic agents.
Presently, there are two types of transdermal drug delivery systems, i.e., "Passive" and "Active." Passive systems deliver drug through the skin of the user unaided, an example of which would involve the application of a topical anesthetic to provide localized relief, as disclosed in U.S. Pat. No. 3,814,095 (Lubens). Active systems on the other hand deliver drug through the skin of the user using, for example, iontophoresis, which according to Stedman's Medical Dictionary, is defined as "the introduction into the tissues, by means of an electric current, of the ions of a chosen medicament." Such systems offer advantages clearly not achievable by any other methods of administration, such as avoiding introduction of the drug through the gastro-intestinal tract or punctures in the skin to name a few.
Conventional iontophoretic devices, such as those described in U.S. Pat. Nos. 5,498,235 (Flower), 5,540,669 (Sage, Jr. et al.), and 5,645,526 (Flower), the disclosures of which are hereby incorporated by reference, for delivering a drug or medicine transdermally through iontophoresis, basically consist of two electrodes, which are in contact with a portion of a patient's body. A first electrode, generally called the active electrode, delivers the ionic substance or drug into the body by iontophoresis. The second electrode, generally called the counter electrode, closes an electrical circuit that includes the first electrode and the patient's body. Generally, the circuit includes a source of electrical energy, such as a battery. The ionic substance to be driven into the body may be either positively charged or negatively charged. In the case of a positively charged ionic substance, the anode of the iontophoretic device becomes the active electrode and the cathode serves as the counter electrode to complete the circuit. Alternatively, if the ionic substance to be iontophoretically delivered is negatively charged, the cathode will be the active electrode and the anode will be the counter electrode.
In practice, this process is typically achieved by placing the ionic drug either in solution or in gel form on a carrier and placing the drug-containing carrier, for example, in the form of a drug-filled adhesive patch, into contact with the skin, with the patch being electrically and mechanically connected to a controller. The controller includes a power source, such as a battery, as well as electrical circuitry required for generating and regulating current applied to the electrodes contained in the patch.
The pair of electrodes is placed in contact with the skin and with the carrier. Direct current is applied between the two electrodes. Under the influence of the electric field present, the drug molecules migrate through the skin. As current flows between the two electrodes placed at spaced apart locations on the skin, the current path carries the drug with it.
In order to deliver the drug to the patient, the adhesive patch may be applied to the desired portion of the patient's body and the controller attached to the patch. Oftentimes the controller is as large as, or larger than, the patch. It also should be somehow secured in place on the patient so that the patient may remain mobile and carry both the patch and controller with him as he moves about.
Delivery of a drug to the patient iontophoretically may be accomplished either at a constant rate over a long period of time, or periodically at various intervals and in some situations, upon demand. As can be seen, it may be necessary for the drug-containing carrier to be maintained in contact with the patient's skin over a long period of time, either for continuous drug delivery, or to permit frequent interval delivery over a period of time.
As previously noted, it may be necessary to use an iontophoretic drug delivery system over an extended period of time i.e., longer than 24 hours to delivery the necessary dosage of drug. As the length of delivery time increases, there is a need to develop small, unobtrusive iontophoretic delivery devices which can be easily worn on the skin under clothing. Also, it is envisioned that the controller may contain sophisticated electronics along with the battery to control and monitor the delivery of drug to the patient.
The output voltage of the battery is often used as an indicator of the energy remaining in the battery. That output voltage may be monitored by a voltage monitoring circuit, either internally connected to the device to which the battery supplies energy or externally connected to that device. The output voltage of some types of batteries, such as alkaline manganese dioxide Zn/MnO.sub.2 batteries (hereinafter referred to as "alkaline" batteries) gradually decreases, as shown in FIG. 1A (corresponding to Fig. 7.5 of the Handbook of Batteries, edited by David Linden, 1984). When the monitoring circuit has detected that the output voltage has decreased below a predetermined voltage level, there might be enough energy left in the battery for the device to complete a critical ongoing task, such as drug delivery in an iontophoretic drug delivery system, as described below, or to perform an essential power-down function, such as memory backup in a battery-powered computer. These types of batteries, however, may not be preferred for certain applications which require batteries with high energy and high current capacity.
Other conventional batteries, such as zinc/silver oxide batteries (Zn/Ag.sub.2 O, hereinafter referred to a "silver oxide batteries"), are characterized by a substantially flat output voltage over time, until the cells of the battery die, at which time the output voltage sharply decreases, as shown by FIG. 1B (corresponding to Fig. 9.4 of the Handbook of Batteries). Despite this discharge characteristic, silver oxide batteries are preferred for certain electrical applications because they are small, thin and light, and deliver a high amount of current for a long period of time. When the voltage monitoring circuit has detected that the output voltage of the battery has begun to decrease sharply, there may not be enough energy left in the battery, however, for the device to complete a critical ongoing task or to perform an essential power-down function. Therefore, there is a need for a high quality, high-current delivering battery, such as the conventional silver oxide battery, which also has enough remaining energy, after the voltage monitoring circuit has detected the sharp decrease in the output voltage, to allow the device to complete its task or to power-down.
Section 8.5.7 of the Handbook of Batteries describes a "stepped-voltage" battery which produces a well-defined step in the output voltage prior to its complete discharge, as shown in FIG. 1C (corresponding to Fig. 8.25 of the Handbook of Batteries). This voltage step occurs well before the end of battery life so that, after the voltage monitoring circuit has detected the voltage step, enough energy remains in the battery to allow the device to complete a final task or to power-down. The stepped-voltage battery is made by using materials in the cathode or the anode of the battery which discharge at a different potential from the base electrode.
In particular, FIG. 1C shows a nine-cell battery having a stepped battery voltage discharge curve V.sub.total, which is produced by serially connecting seven zinc/mercuric oxide cells that together are characterized by the substantially flat voltage discharge curve V.sub.2, and two hybrid cells that together are characterized by the stepped voltage discharge curve V.sub.1. The hybrid cells have cathodes in which part of the mercuric oxide has been replaced by cadmium oxide in a sufficient quantity to leave each hybrid cell with the same balanced capacity. When all of the mercuric oxide has been reduced in the hybrid cells, that is, the hybrid cells have discharged, their combined voltage falls by 1.5 Volts (750 millivolt per hybrid cell), as shown in curve V.sub.1. This causes the combined voltage V.sub.total to decrease by 1.5 Volts. This sudden, large drop in the output voltage can be easily detected by the voltage monitoring circuit, and thus can serve to trigger an alarm indicating the need for battery replacement, or to warn the device that any ongoing task should be a final task or that the device should begin powering down. The size of the voltage step can be adjusted, for example, by increasing or decreasing the number of hybrid cells in the battery. Further, during manufacture of the stepped-voltage battery, the voltage step can be arranged to occur at varying points during the life of the battery. For example, in the nine-cell battery of FIG. 1C, the voltage step was arranged to occur at about 60% (650 hours) of the overall life (1100 hours).
The above-described stepped-voltage batteries are, however, limited in their use, especially as a substitute for silver oxide batteries and the like. First, all the cells of the stepped-voltage battery are arranged in a relatively large, wide and heavy package, making its use impractical for small or thin electronic devices. Second, relative to silver oxide batteries, stepped-voltage batteries are expensive and have a lower current capacity. Third, to meet all of the different energy requirements of various devices, a device manufacturer would need to order and stock, unfortunately, many different types of stepped-voltage batteries. Finally, although the time at which the voltage step of the stepped-voltage battery occurs can be set as described above, that setting is set during manufacturing and cannot be adjusted thereafter. It would be more desirable to be able to use a battery with which the time of the voltage step can be adjusted while the device is being operated. Such time adjustment can be based on the operating conditions of the device using, for example, computer control.
Thus, there has been a need for an iontophoretic drug delivery system, particularly a controller which would eliminate the problems and limitations associated with the prior devices discussed above, most significant of the problems being the need for a time-adjustable, stepped-voltage output when use of a more practical and desirable conventional battery, such as a silver oxide battery, is required by the device.